Long-term pharmacokinetic and pharmacological evaluations of a novel indole-benzazepinone derivative on obese Type 2 diabetes mellitus.

Background: Owing to the chronic nature of Type 2 diabetes mellitus, antidiabetic drugs must have long-lasting efficacy. Compound 1 has a good inhibitory effect on acute hyperglycemia, but its long-term hypoglycemic effect has not been evaluated. Results: Preliminary prediction and in vitro experimental pharmacokinetic results support the use of compound 1 for long-term in vivo experiments. Long-term experiments demonstrated that compound 1 significantly reduces blood glucose, improves the oral glucose tolerance of obese mice and has a positive effect on body weight, free fatty acid, hepatocyte steatosis and inflammatory cell infiltration. Conclusion: These findings lay a good foundation for the further exploration and development of novel glycogen phosphorylase inhibitors.

The influence of droplet concentration on phase change and inertial cavitation thresholds associated with acoustic droplet vaporization.

Acoustic droplet vaporization (ADV) is an important process that enables the theragnostic application of acoustically activated droplets, where the nucleation of inertial cavitation (IC) activity must be precisely controlled. This Letter describes threshold pressure measurements for ADV and acoustic emissions consistent with IC activity of lipid-shelled non-superheated perfluoropentane nanodroplets over a range of physiologically relevant concentrations at 1.1-MHz. Under the frequency investigated, results show that the thresholds were relatively independent of concentration for intermediate concentrations (105, 106, and 107 droplets/ml), thus indicating an optimal range of droplet concentrations for conducting threshold studies. For the highest concentration, the difference between the threshold for IC and the threshold for ADV was greatly reduced, suggesting that it might prove difficult to induce ADV without concomitant IC in applications that employ higher concentrations.

A Human Microrobot Interface Based on Acoustic Manipulation.

Micro/nanorobotic systems capable of targeted transporting and releasing hold considerable promise for drug delivery, cellular surgery, biosensing, nano assembling, etc. However, on-demand precise control of the micro/nanorobot movement remains a major challenge. In particular, a practical interface to realize instant and customized interactions between human and micro/nanorobots, which is quite essential for developing next generation intelligent micro/nanorobots, has seldom been explored. Here, we present a human-microrobot user interface to perform direct and agile recognition of user commands and signal conversion for driving the microrobot. The microrobot platform is built based on locally enhanced acoustic streaming which could precisely transport microparticles and cells along a given pathway, while the interface is enabled by tuning the actuation frequency and time with different instructions and inputs. Our numerical simulations and experimental demonstrations illustrate that microparticles can be readily transported along the path by the acoustic robotic system, due to the vibration-induced locally enhanced acoustic streaming and resultant propulsion force. The acoustic robotic platform allows large-scale parallel transportation for microparticles and cells along given paths. The human microrobot interface enables the micromanipulator to response promptly to the users' commands input by typing or music playing for accurate transport. For example, the music tone of a playing melody is used for manipulating a cancer cell to a targeted position. The interface offers several attractive capabilities, including tunable speed and orientation, quick response, considerable delivery capacities, high precision and favorable controllability. We expect that such interface will work as a compelling and versatile platform for myriad potential scenarios in transportation units of microrobots, single cell analysis instruments, lab-on-chip systems, microfactories, etc.

Photo- and Sono-Dynamic Therapy: A Review of Mechanisms and Considerations for Pharmacological Agents Used in Therapy Incorporating Light and Sound.

As irreplaceable energy sources of minimally invasive treatment, light and sound have, separately, laid solid foundations in their clinic applications. Constrained by the relatively shallow penetration depth of light, photodynamic therapy (PDT) typically involves involves superficial targets such as shallow seated skin conditions, head and neck cancers, eye disorders, early-stage cancer of esophagus, etc. For ultrasound-driven sonodynamic therapy (SDT), however, to various organs is facilitated by the superior... transmission and focusing ability of ultrasound in biological tissues, enabling multiple therapeutic applications including treating glioma, breast cancer, hematologic tumor and opening blood-brain-barrier (BBB). Considering the emergence of theranostics and precision therapy, these two classic energy sources and corresponding sensitizers are worth reevaluating. In this review, three typical therapies using light and sound as a trigger, PDT, SDT, and combined PDT and SDT are introduced. The therapeutic dynamics and current designs of pharmacological sensitizers involved in these therapies are presented. By introducing both the history of the field and the most up-to-date design strategies, this review provides a systemic summary on the development of PDT and SDT and fosters inspiration for researchers working on 'multi-modal' therapies involving light and sound.

Cell-cycle-dependences of membrane permeability and viability observed for HeLa cells undergoing multi-bubble-cell interactions.

Microbubble-mediated sonoporation is a promising strategy for intracellular gene/drug delivery, but the biophysical mechanisms involved in the interactions between microbubbles and cells are not well understood. Here, HeLa cells were synchronized in individual cycle phases, then the cell-cycle-dependences of the membrane permeability and viability of HeLa cells undergoing multi-bubble sonoporation were evaluated using focused ultrasound exposure apparatus coupled passive cavitation detection system. The results indicated that: (1) the microbubble cavitation activity should be independent on cell cycle phases; (2) G1-phase cells with the largest Young's modulus were the most robust against microbubble-mediated sonoporation; (3) G2/M-phase cells exhibited the greatest accumulated FITC uptake with the lowest viability, which should be mainly attributed to the chemical effect of synchronization drugs; and (4) more important, S-phase cells with the lowest stiffness seemed to be the most susceptible to the mechanical effect generated by microbubble cavitation activity, which resulted in the greatest enhancement in sonoporation-facilitated membrane permeabilization without further scarifying their viability. The current findings may benefit ongoing efforts aiming to pursue rational utilization of microbubble-mediated sonoporation in cell-cycle-targeted gene/drug delivery for cancer therapy.

The enhanced HIFU-induced thermal effect via magnetic ultrasound contrast agent microbubbles.

High intensity focused ultrasound (HIFU) has been regarded as a promising technology for treating cancer and other severe diseases noninvasively. In the present study, dual modality magnetic ultrasound contrast agent microbubbles (MBs) were synthesized by loading the super paramagnetic iron oxide nanoparticles (SPIOs) into the albumin-shelled MBs (referred as SPIO-albumin MBs). Then, both experimental measurements and numerical simulations were performed to evaluate the ability of SPIO-albumin MBs of enhancing HIFU-induced thermal effect. The results indicated that, comparing with regular albumin-shelled MBs, the SPIO-albumin MBs would lead to quicker temperature elevation rate and higher peak temperature. This phenomenon could be explained by the changes in MBs' physical and thermal properties induced by the integration of SPIOs into MB shell materials. In addition, more experimental results demonstrated that the enhancement effect on HIFU-induced temperature elevation could be further strengthened with more SPIOs combined with albumin-shell MBs. These observations suggested that more violent cavitation behaviors might be activated by ultrasound exposures with the presence of SPIOs, which in turn amplified ultrasound-stimulated thermal effect. Based on the present studies, it is reasonable to expect that, with the help of properly designed dual-modality magnetic MBs, the efficiency of HIFU-induced thermal effect could be further improved to achieve better therapeutic outcomes.

Cell-cycle-specific Cellular Responses to Sonoporation.

Microbubble-mediated sonoporation has shown its great potential in facilitating intracellular uptake of gene/drugs and other therapeutic agents that are otherwise difficult to enter cells. However, the biophysical mechanisms underlying microbubble-cell interactions remain unclear. Particularly, it is still a major challenge to get a comprehensive understanding of the impact of cell cycle phase on the cellular responses simultaneously occurring in cell membrane and cytoskeleton induced by microbubble sonoporation. Methods: Here, efficient synchronizations were performed to arrest human cervical epithelial carcinoma (HeLa) cells in individual cycle phases. The, topography and stiffness of synchronized cells were examined using atomic force microscopy. The variations in cell membrane permeabilization and cytoskeleton arrangement induced by sonoporation were analyzed simultaneously by a real-time fluorescence imaging system. Results: The results showed that G1-phase cells typically had the largest height and elastic modulus, while S-phase cells were generally the flattest and softest ones. Consequently, the S-Phase was found to be the preferred cycle for instantaneous sonoporation treatment, due to the greatest enhancement of membrane permeability and the fastest cytoskeleton disassembly at the early stage after sonoporation. Conclusion: The current findings may benefit ongoing efforts aiming to pursue rational utilization of microbubble-mediated sonoporation in cell cycle-targeted gene/drug delivery for cancer therapy.